Synthesis, Chemistry, and Antineoplastic Activity of α-Halopyridinium Salts: Potential Pyridone Prodrugs of Acylated Vinylogous Carbinolamine Tumor Inhibitors

A series of 4- and 5-[2,3-dihydro-6,7-bis[[(N-alkylcarbamoyl)oxy]methyl]-lH-pyrrolizin-5-yl]-2-halopyridinium iodides were synthesized. The rates of hydrolysis of the α-halopyridinium salts to the corresponding pyridones, and the reactivities of the carbamate moieties were studied as a function of pH, buffer composition, and ionic strength. The 4- and 5-pyrrolizinyl-2-halopyridinium iodides and the corresponding pyridones were evaluated against P388 lymphocytic leukemia in vivo. The a-fluoropyridinium compounds were active but the a-chloro compounds were not. This activity was correlated with the rates of hydrolysis of the a-halopyridinium compounds to the active pyridone. Compounds that were active in the P388 screen were evaluated in L1210 leukemia, M5076 carcinoma, and MX-1 mammary xenograft assays in mice.